tbuckley/cabot-search huggingface dataset:
Disparities in Multisystem Inflammatory Syndrome in Children and COVID-19 Across the Organ Dysfunction Continuum
Authors: Blake Martin, Suchitra Rao, Tellen D. Bennett
Journal: JAMA Network Open (2023)

The most serious sequela of pediatric SARS-CoV-2 is multisystem inflammatory syndrome in children (MIS-C).Occurring 2 to 6 weeks after SARS-CoV-2 infection, MIS-C is characterized by a severe systemic inflammatory response manifesting with fever and multiple organ system dysfunctions.2][3] Prior studies identified demographic and comorbidity risk factors and differing patterns of organ dysfunction when comparing MIS-C with pediatric COVID-19. 1,2However, specific analyses evaluating interactions of social vulnerability, race and ethnicity, and extent of MIS-C and COVID-19 severity by number of organ systems involved have been lacking.In their article, Encinosa et al 4 leverage cost and health care usage data from the Agency for Healthcare Research and Quality to perform a cross-sectional study evaluating demographic characteristics, clinical outcomes, adverse medication events (AMEs), and hospital costs of children with MIS-C and COVID-19, with specific attention to the number of organ systems involved.The authors evaluate how these outcomes vary with increasing patient social vulnerability as measured by the Centers for Disease Control and Infection Social Vulnerability Index (SVI) determined at the county level through a combination of 15 socioeconomic, disability, language, and transportation access variables.The authors used the MIS-C International Statistical Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) diagnosis code (M35.81) to identify 4107 children with MIS-C across 4057 community hospitals in 31 states included in the data set (covering 77% of the US population).In their study, we are provided with a more complete picture of the clinical and usage outcomes of MIS-C and pediatric COVID-19 with specific attention to risk profiles informed by social, demographic, and economic factors.
Implications and prognostic impact of mass spectrometry in patients with newly-diagnosed multiple myeloma
Authors: Elias K. Mai, Stefanie Huhn, Kaya Miah, Alexandra M. Poos, Christof Scheid, Katja C. Weisel, Uta Bertsch, Markus Munder, Oscar Berlanga, Dirk Hose, Anja Seckinger, Anna Jauch, Igor W. Blau, Mathias Hänel, Hans J. Salwender, Axel Benner, Marc S. Raab, Hartmut Goldschmidt, Niels Weinhold
Journal: Blood Cancer Journal (2023)

Abstract Mass spectrometry (MS) is a promising tool for monitoring monoclonal protein in plasma cell dyscrasias. We included 480 transplant-eligible newly-diagnosed multiple myeloma (MM) patients from the GMMG-MM5 trial (EudraCT No. 2010-019173-16) and performed a retrospective MS analysis at baseline (480 patients) and at the pre-defined, consecutive time points after induction (444 patients), prior to maintenance (305 patients) and after one year of maintenance (227 patients). We found that MS negativity was significantly associated with improved progression-free survival (PFS) even in patients with complete response (CR) at all investigated follow-up time points. The prognostic impact was independent of established risk factors, such as the revised International Staging System. Combining MS and baseline cytogenetics improved the prediction of outcome: MS-positive patients with high-risk cytogenetics had a dismal PFS of 1.9 years (95% confidence interval [CI]: 1.6–2.3 years) from the start of maintenance. Testing the value of sequential MS prior to and after one year of maintenance, patients converting from MS positivity to negativity had an excellent PFS (median not reached) while patients converting from MS negativity to positivity progressed early (median 0.6 years, 95% CI: 0.3-not reached). Among patients with sustained MS positivity, the baseline high-risk cytogenetic status had a significant impact and defined a group with poor PFS. Combining minimal residual disease (MRD) in the bone marrow and MS allowed the identification of double negative patients with a favorable PFS (median 3.33 years, 95% CI: 3.08-not reached) and no overall survival events. Our study provides strong evidence that MS is superior to conventional response monitoring, highlighting the potential of MS to become a new standard. Our data indicate that MS should be performed sequentially and combined with baseline disease features and MRD to improve its clinical value. Clinical Trials Register: EudraCT No. 2010-019173-16
Regulatory T cells suppress CD4+ effector T cell activation by controlling protein synthesis
Authors: Lomon So, Kazushige Obata-Ninomiya, Alex Hu, Virginia S. Muir, Ayako Takamori, Jing Song, Jane H. Buckner, Ram Savan, Steven F. Ziegler
Journal: The Journal of Experimental Medicine (2023)

Regulatory T cells (Tregs) suppress the activation and subsequent effector functions of CD4 effector T cells (Teffs). However, molecular mechanisms that enforce Treg-mediated suppression in CD4 Teff are unclear. We found that Tregs suppressed activation-induced global protein synthesis in CD4 Teffs prior to cell division. We analyzed genome-wide changes in the transcriptome and translatome of activated CD4 Teffs. We show that mRNAs encoding for the protein synthesis machinery are regulated at the level of translation in activated CD4 Teffs by Tregs. Tregs suppressed global protein synthesis of CD4 Teffs by specifically inhibiting mRNAs of the translation machinery at the level of mTORC1-mediated translation control through concerted action of immunosuppressive cytokines IL-10 and TGFβ. Lastly, we found that the therapeutic targeting of protein synthesis with the RNA helicase eIF4A inhibitor rocaglamide A can alleviate inflammatory CD4 Teff activation caused by acute Treg depletion in vivo. These data show that peripheral tolerance is enforced by Tregs through mRNA translational control in CD4 Teffs.
The neuropeptide CGRP enters the macrophage cytosol to suppress the NLRP3 inflammasome during pulmonary infection
Authors: Fangrui Zhu, Dou Yu, Xiwen Qin, Yan Qian, Juan Ma, Weitao Li, Qiannv Liu, Chunlei Wang, Yan Zhang, Yi Li, Dong Jiang, Shuo Wang, Pengyan Xia
Journal: Cellular and Molecular Immunology (2023)
More COACHing Needed to Optimize Care after Heart Failure Hospitalization
Authors: Parag Goyal, Evelyn M. Horn
Journal: New England Journal of Medicine (2023)

Despite two decades of research, outcomes after hospitalizations for heart failure remain poor.1 Myriad interventions have been studied, yet most have failed to consistently improve outcomes.2 For example, tools to stratify risk exist, but their effect has been limited by modest predictive performance and uncertainty regarding how best to modify risk. Early follow-up after hospital discharge is recommended as a strategy to improve outcomes, but broad uptake has not occurred, in part because of limited resources. Through the Comparison of Outcomes and Access to Care for Heart Failure (COACH) trial, the results of which are published in this issue of . . .
Moving the Needle on Alzheimer’s Disease with an Anti-Oligomer Antibody
Authors: Sam Gandy, Michelle E. Ehrlich
Journal: New England Journal of Medicine (2023)

In the current issue of the Journal, van Dyck and colleagues1 report the encouraging results of an 18-month, phase 3 trial of lecanemab that involved participants with early Alzheimer's disease. The primary end point was the change from baseline in the score on the Clinical Dementia Rating–Sum of Boxes. Key secondary end points were the change from baseline in amyloid burden as assessed by means of positron emission tomography, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale, the Alzheimer's Disease Composite Score, and the score on the Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale . . .
Human soft tissue sarcomas harbor an intratumoral viral microbiome which is linked with natural killer cell infiltrate and prognosis
Authors: Lauren M Perry, Sylvia M Cruz, Kara T Kleber, Sean J Judge, Morgan A Darrow, Louis B Jones, Ugur N Basmaci, Nikhil Joshi, Matthew L Settles, Blythe P Durbin-Johnson, Alicia A Gingrich, Arta Monir Monjazeb, Janai Carr-Ascher, Steve W Thorpe, William J Murphy, Jonathan A Eisen, Robert J Canter
Journal: Journal for ImmunoTherapy of Cancer (2023)

Groundbreaking studies have linked the gut microbiome with immune homeostasis and antitumor immune responses. Mounting evidence has also demonstrated an intratumoral microbiome, including in soft tissue sarcomas (STS), although detailed characterization of the STS intratumoral microbiome is limited. We sought to characterize the intratumoral microbiome in patients with STS undergoing preoperative radiotherapy and surgery, hypothesizing the presence of a distinct intratumoral microbiome with potentially clinically significant microbial signatures.We prospectively obtained tumor and stool samples from adult patients with non-metastatic STS using a strict sterile collection protocol to minimize contamination. Metagenomic classification was used to estimate abundance using genus and species taxonomic levels across all classified organisms, and data were analyzed with respect to clinicopathologic factors.Fifteen patients were enrolled. Most tumors were located at an extremity (67%) and were histologic grade 3 (87%). 40% were well-differentiated/dedifferentiated liposarcoma histology. With a median follow-up of 24 months, 4 (27%) patients developed metastases, and 3 (20%) died. Despite overwhelming human DNA (>99%) intratumorally, we detected a small but consistent proportion of bacterial DNA (0.02-0.03%) in all tumors, including Proteobacteria, Bacteroidetes, and Firmicutes, as well as viral species. In the tumor microenvironment, we observed a strong positive correlation between viral relative abundance and natural killer (NK) infiltration, and higher NK infiltration was associated with superior metastasis-free and overall survival by immunohistochemical, flow cytometry, and multiplex immunofluorescence analyses.We prospectively demonstrate the presence of a distinct and measurable intratumoral microbiome in patients with STS at multiple time points. Our data suggest that the STS tumor microbiome has prognostic significance with viral relative abundance associated with NK infiltration and oncologic outcome. Additional studies are warranted to further assess the clinical impact of these findings.
The prevalence and outcomes of frail older adults in clinical trials in multiple myeloma: A systematic review
Authors: Hira Mian, Arleigh McCurdy, Smith Giri, Shakira Grant, Bram Rochwerg, Erica Winks, Ashley E. Rosko, Monika Engelhardt, Charlotte Pawlyn, Gordon Cook, Graham Jackson, Sara Bringhen, Thierry Facon, Alessandra Larocca, Sonja Zweegman, Tanya M. Wildes
Journal: Blood Cancer Journal (2023)

Abstract Multiple myeloma (MM) is an incurable blood cancer that primarily affects older adults. Several frailty tools have been developed to address the heterogeneity of aging in this population. Uptake of these measures has been variable, leading to a gap in knowledge regarding the proportion of enrolled trial participants considered frail and uncertainty in the treatment-related effects and outcomes among this high-risk population. We performed a systematic review of therapeutic interventional MM clinical trials reporting on frailty. We included 43 clinical trials (24 randomized controlled trials and 19 non-randomized trials) which met eligibility criteria. Frailty was increasingly incorporated in studies in more recent years with 41.9% of included studies being reported in the last two years. Commonly used frailty tools included the International Myeloma Working Group (IMWG) frailty index (41.8%), and the simplified frailty score (39.5%). Frailty status was categorized with 3 levels as (frail, intermediate fit, or fit) in 51.2% of the studies and dichotomized (frail, non-frail) in 18.6% of studies. Frailty prevalence greatly varied across trials ranging from 17.2% to 73.6% of the cohort. Of the included studies, 72.0% conducted subgroup analysis (planned or post-hoc) based on frailty status. Most studies demonstrated a consistent benefit of MM interventions among the frail and non-frail populations, however in general, frail patients had worse outcomes compared to the fit. Although frailty is increasingly being incorporated in MM clinical trials, due to the variation in both the definition and categorization of frailty, there remains heterogeneity in the prevalence of frailty and its potential associated impact on outcomes.
Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations
Authors: Elise Marsan, Dmitry Velmeshev, Arren Ramsey, Ravi K. Patel, Jiasheng Zhang, Mark Koontz, Madeline G. Andrews, Martina de Majo, Cristina Mora, Jessica Blumenfeld, Alissa N. Li, Salvatore Spina, Lea T. Grinberg, William W. Seeley, Bruce L. Miller, Erik M. Ullian, Matthew F. Krummel, Arnold R. Kriegstein, Eric J. Huang
Journal: Journal of Clinical Investigation (2023)

Mutations in the human Progranulin (GRN) gene are a leading cause of frontotemporal lobar degeneration (FTLD). While previous studies implicate aberrant microglial activation as a disease-driving factor in neurodegeneration in the thalamocortical circuit in Grn-/- mice, the exact mechanism for neurodegeneration in FTLD-GRN remains unclear. By performing comparative single-cell transcriptomics in the thalamus and frontal cortex of Grn-/- mice and patients with FTLD-GRN, we have uncovered a highly conserved astroglial pathology characterized by upregulation of gap junction protein GJA1, water channel AQP4, and lipid-binding protein APOE, and downregulation of glutamate transporter SLC1A2 that promoted profound synaptic degeneration across the two species. This astroglial toxicity could be recapitulated in mouse astrocyte-neuron cocultures and by transplanting induced pluripotent stem cell-derived astrocytes to cortical organoids, where Progranulin-deficient astrocytes promoted synaptic degeneration, neuronal stress, and TDP-43 proteinopathy. Together, these results reveal previously unappreciated astroglial pathology as a key mechanism in neurodegeneration in FTLD-GRN.
Natural killer cells for antiviral therapy
Authors: Davey M. Smith, Jolie R. Schafer, Brian Tullius, Laura Witkam, Silke Paust
Journal: Science Translational Medicine (2023)

Natural killer (NK) cell-based immunotherapy is being explored for treating infectious diseases, including viral infections. Here, we discuss evidence of NK cell responses to different viruses, ongoing clinical efforts to treat such infections with NK cell products, and review platforms to generate NK cell products.
Analysis of Tumor Mutational Burden, Progression-Free Survival, and Local-Regional Control in Patients with Locally Advanced Non–Small Cell Lung Cancer Treated With Chemoradiation and Durvalumab
Authors: Emily S. Lebow, Annemarie Shepherd, Jordan E. Eichholz, Michael Offin, Daphna Y. Gelblum, Abraham J. Wu, Charles B. Simone, Adam J. Schoenfeld, David R. Jones, Andreas Rimner, Jamie E. Chaft, Nadeem Riaz, Daniel R. Gomez, Narek Shaverdian
Journal: JAMA Network Open (2023)

Importance The addition of consolidative durvalumab to chemoradiation has improved disease control and survival in locally advanced non–small cell lung cancer (NSCLC). However, there remains a need to identify biomarkers for response to this therapy to allow for risk adaptation and personalization. Objectives To evaluate whether TMB or other variants associated with radiation response are also associated with outcomes following definitive chemoradiation and adjuvant durvalumab among patients with locally advanced unresectable NSCLC. Design, Setting, and Participants This cohort study included consecutive patients with unresectable locally advanced NSCLC treated with chemoradiation and adjuvant durvalumab between November 2013 and March 2020 who had prospective comprehensive genomic profiling. This study was completed at a multisite tertiary cancer center. The median (IQR) follow-up time was 26 (21-36) months. Statistical analysis was conducted from April to October 2022. Exposures Patients were grouped into TMB-high (≥10 mutations/megabase [mt/Mb]) and TMB-low (&amp;amp;lt;10 mt/Mb) groups and were additionally evaluated by the presence of somatic alterations associated with radiation resistance ( KEAP1 / NFE2L2 ) or radiation sensitivity (DNA damage repair pathway). Main Outcomes and Measures The primary outcomes were 24-month local-regional failure (LRF) and progression-free survival (PFS). Results In this cohort study of 81 patients (46 [57%] male patients; median [range] age, 67 [45-85] years), 36 patients (44%) had TMB-high tumors (≥10 mt/Mb). Patients with TMB-high vs TMB-low tumors had markedly lower 24-month LRF (9% [95% CI, 0%-46%] vs 51% [95% CI, 36%-71%]; P = .001) and improved 24-month PFS (66% [95% CI, 54%-84%] vs 27% [95% CI, 13%-40%]; P = .003). The 24-month LRF was 52% (95% CI, 25%-84%) among patients with KEAP1/NFE2L2 -altered tumors compared with 27% (95% CI, 17%-42%) among patients with KEAP1/NFE2L2 -wildtype tumors ( P = .05). On Cox analysis, only TMB status was associated with LRF (hazard ratio [HR], 0.17; 95% CI, 0.03-0.64; P = .02) and PFS (HR, 0.45; 95% CI, 0.21-0.90; P = .03). Histology, disease stage, Eastern Cooperative Oncology Group status, programmed cell death ligand 1 expression, and pathogenic KEAP1/NFE2L2 , KRAS , and DNA damage repair pathway alterations were not significantly associated with LRF or PFS. Conclusions and Relevance In this cohort study, TMB-high status was associated with improved local-regional control and PFS after definitive chemoradiation and adjuvant durvalumab. TMB status may facilitate risk-adaptive radiation strategies in unresectable locally advanced NSCLC.
Nanostructured multifunctional stimuli-responsive glycopolypeptide-based copolymers for biomedical applications
Authors: Mahsa Sedighi, Zahra Mahmoudi, Alireza Ghasempour, Mehdi Shakibaie, Fahimeh Ghasemi, Mahsa Akbari, Samin Abbaszadeh, Ebrahim Mostafavi, Hélder A. Santos, Mohammad-Ali Shahbazi
Journal: Journal of Controlled Release (2023)

Inspired by natural resources, such as peptides and carbohydrates, glycopolypeptide biopolymer has recently emerged as a new form of biopolymer being recruited in various biomedical applications. Glycopolypeptides with well-defined secondary structures and pendant glycosides on the polypeptide backbone have sparked lots of research interest and they have an innate ability to self-assemble in diverse structures. The nanostructures of glycopolypeptides have also opened up new perspectives in biomedical applications due to their stable three-dimensional structures, high drug loading efficiency, excellent biocompatibility, and biodegradability. Although the development of glycopolypeptide-based nanocarriers is well-studied, their clinical translation is still limited. The present review highlights the preparation and characterization strategies related to glycopolypeptides-based copolymers, followed by a comprehensive discussion on their biomedical applications with a specific focus on drug delivery by various stimuli-responsive (e.g., pH, redox, conduction, and sugar) nanostructures, as well as their beneficial usage in diagnosis and regenerative medicine.
Postoperative Restrictive Opioid Protocols and Durable Changes in Opioid Prescribing and Chronic Opioid Use
Authors: Emese Zsiros, Jason Ricciuti, Steven Gallo, Deanna Argentieri, Kristopher Attwood, Wenyan Ji, Alan Hutson, Paul Visco, Devon Coffey, Grazyna Riebandt, Jaron Mark, Aaron Varghese, Suzanne M. Hess, Thomas Furlani, Andrew Fabiano, Mark Hennon, Sai Yendamuri, Eric C. Kauffman, Kimberly E. Wooten, Wesley L. Hicks, Jessica Young, Kazuaki Takabe, Kunle Odunsi, Amy A. Case, Brahm H. Segal, Candace S. Johnson, Boris Kuvshinoff, Steven Nurkin, Gyorgy Paragh, Oscar de Leon-Casasola
Journal: JAMA Oncology (2023)

Changes in postsurgical opioid prescribing practices may help reduce chronic opioid use in surgical patients.
One-year breakthrough SARS-CoV-2 infection and correlates of protection in fully vaccinated hematological patients
Authors: José Luis Piñana, Lourdes Vazquez, Marisa Calabuig, Lucia López-Corral, Gabriel Martin-Martin, Lucia Villalon, Gabriela Sanz-Linares, Venancio Conesa-Garcia, Andrés Sanchez-Salinas, Beatriz Gago, Ana Facal, Irene Risco-Gálvez, María T. Olave, Ildefonso Espigado, Javier Lopez-Jimenez, José Ángel Hernández-Rivas, Alejandro Avendaño-Pita, Ignacio Arroyo, Elena Ferrer, Irene García-Cadenas, Clara González-Santillana, Alicia Roldán-Pérez, Blanca Ferrer, Manuel Guerreiro, María Suarez-Lledó, Angela Camara, Diana Campos-Beltrán, David Navarro, Ángel Cedillo, Anna Sureda, Carlos Solano, Rodrigo Martino
Journal: Blood Cancer Journal (2023)

Abstract The long-term clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has been little explored. A prospective multicenter registry-based cohort study conducted from December 2020 to July 2022 by the Spanish Transplant and Cell Therapy group, was used to analyze the relationship of antibody response over time after full vaccination (at 3–6 weeks, 3, 6 and 12 months) (2 doses) and of booster doses with breakthrough SARS-CoV-2 infection in 1551 patients with hematological disorders. At a median follow-up of 388 days after complete immunization, 266 out of 1551 (17%) developed breakthrough SARS-CoV-2 infection at median of 86 days (range 7–391) after full vaccination. The cumulative incidence was 18% [95% confidence interval (C.I.), 16–20%]. Multivariate analysis identified higher incidence in chronic lymphocytic leukemia patients (29%) and with the use of corticosteroids (24.5%), whereas female sex (15.5%) and more than 1 year after last therapy (14%) were associated with a lower incidence (p &lt; 0.05 for all comparisons). Median antibody titers at different time points were significantly lower in breakthrough cases than in non-cases. A serological titer cut-off of 250 BAU/mL was predictive of breakthrough infection and its severity. SARS-CoV-2 infection-related mortality was encouragingly low (1.9%) in our series. Our study describes the incidence of and risk factors for COVID-19 breakthrough infections during the initial vaccination and booster doses in the 2021 to mid-2022 period. The level of antibody titers at any time after 2-dose vaccination is strongly linked with protection against both breakthrough infection and severe disease, even with the Omicron SARS-CoV-2 variant.